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Abstract

Background

Streptococcus pneumoniae is the bacterial agent which most frequently causes pneumonia. In some Scandinavian
countries, this infection is treated with penicillin V since the resistances of pneumococci
to this antibiotic are low. Four reasons justify the undertaking of this study; firstly,
the cut-off points which determine whether a pneumococcus is susceptible or resistant
to penicillin have changed in 2008 and according to some studies published recently
the pneumococcal resistances to penicillin in Spain have fallen drastically, with
only 0.9% of the strains being resistant to oral penicillin (minimum inhibitory concentration>2 μg/ml);
secondly, there is no correlation between pneumococcal infection by a strain resistant
to penicillin and therapeutic failure in pneumonia; thirdly, the use of narrow-spectrum
antibiotics is urgently needed because of the dearth of new antimicrobials and the
link observed between consumption of broad-spectrum antibiotics and emergence and
spread of antibacterial resistance; and fourthly, no clinical study comparing amoxicillin
and penicillin V in pneumonia in adults has been published. Our aim is to determine
whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment
of uncomplicated community-acquired pneumonia.

Methods

We will perform a parallel group, randomised, double-blind, trial in primary healthcare
centres in Spain. Patients aged 18 to 65 without significant associated comorbidity
attending the physician with signs and symptoms of lower respiratory tract infection
and radiological confirmation of the diagnosis of pneumonia will be randomly assigned
to either penicillin V 1.6 million units thrice-daily during 10 days or amoxicillin
1,000 mg thrice-daily during 10 days. The main outcome will be clinical cure at 14 days,
defined as absence of fever, resolution or improvement of cough, improvement of general
wellbeing and resolution or reduction of crackles indicating that no other antimicrobial
treatment will be necessary. Any clinical result other than the anterior will be considered
as treatment failure. A total of 210 patients will be recruited to detect a non-inferiority
margin of 15% between the two treatments with a minimum power of 80% considering an
alpha error of 2.5% for a unilateral hypothesis and maximum possible losses of 15%.

Discussion

This pragmatic trial addresses the long-standing hypothesis that the administration
of high doses of a narrow-spectrum antibiotic (penicillin V) in patients with non-severe
pneumonia attended in the community is not less effective than high doses of amoxicillin
(treatment currently recommended) in patients under the age of 65 years.

Trial registration

Keywords:

Community-acquired pneumonia; Penicillin; Amoxicillin; Adult

Background

Streptococcus pneumoniae is the bacterial agent which most frequently causes respiratory tract infections.
Indeed, it is the most common bacteria in acute sinusitis, acute otitis media and
community-acquired pneumonia. In some European countries, mainly those located in
Northern Europe, pneumonia is treated with penicillin V since the resistances of these
pneumococci to this antibiotic are low [1]. In the last years a phenomenon of greater community prescription of broad-spectrum
antibiotics has been taking place in many countries, with amoxicillin-clavulanate
and amoxicillin being the antibiotics most frequently prescribed by family practitioners
in Spain [2,3]. Antimicrobial resistance may be a cause of therapeutic failure. It is identified
by measuring the minimum inhibitory concentration (MIC) of the antimicrobial agent
able to inhibit the growth of the microorganism. The cut-off points are MICs which
define the infections as susceptible (treatable), with intermediate resistance (possibly
treatable with higher doses) and resistant (not treatable). After re-evaluation taking
new clinical studies into account, in January 2008 the Clinical and Laboratory Standards Institute published new cut-offs for penicillin [4]. These new cut-off points were determined on the basis of a series of criteria: first,
by the pharmacokinetic and pharmacodynamic properties of the antimicrobial agents
and second, by the data published relating MICs to the clinical outcome of the patients
with pneumococcal infections. With the previous criteria a pneumococcus was considered
to be susceptible with an MIC<0.06 μg/ml, to have intermediate resistance at between
0.12 and 2 μg/ml and to be resistant when the MIC was >2 μg/ml. At present, the new
cut-off points for patients with meningitis receiving endovenous penicillin are <2,
4 and >8 μg/ml, respectively, unifying penicillin and amoxicillin. According to the
results of the SAUCE 4 study published in 2010, the pneumococcal resistances to penicillin
in Spain have fallen drastically, with only 0.9% of the strains being resistant to
oral penicillin (MIC>2 μg/ml) [5]. In view of these results pneumonia could be treated with penicillin in Spain. In
US the American Society of Infectious Diseases also recommends that patients with
pneumonia be treated with penicillin if the causative strain of the infection is susceptible
to this antibiotic [6].

Study justification

Four reasons justify the undertaking of this study and these are: a) as mentioned
above the cut-off points which determine whether a pneumococcus is susceptible or
resistant to penicillin have changed; b) there is no correlation between pneumococcal
infection by a strain resistant to penicillin and therapeutic failure in pneumonia.
Treatment failure has been described in pneumonias treated with macrolides and fluoroquinolones.
Curiously however, in contrast with the latter, in a review of clinical failures due
to antimicrobial resistance no cases of therapeutic failure were reported with β-lactams
prescribed at adequate doses [7]. It is important to know that a large proportion of patients die because of the severity
of their disease and the associated comorbidity but not due to failure of the antibiotic.
Thus, the study by Pallarés et al. has provided evidence that the risk of death by pneumococcal pneumonia treated with
bencilpenicillin or ampicillin was similar regardless of whether the patients were
infected with germs resistant or not to penicillin [8]. In other studies evaluating the effectiveness of penicillin in monotherapy for the
treatment of non-meningeal pneumococcal infections within the first 48 hours in adults,
an increase in mortality was not observed when the infection was caused by a strain
with an MIC<2 μg/ml [9]. c) It is urgent to return to the use of reduced spectrum antibiotics. The increase
in the use of broad-spectrum antibacterial agents has been accompanied by an increase
in the rates of resistances of the microorganisms [10]. Moreover, the incidence of infection by Clostridium difficile is rising in parallel with an increase in the prescription of wide spectrum antibiotics
[11]. d) No clinical study comparing amoxicillin and penicillin V in pneumonia in adults
has been published. Amoxicillin is the first-choice option antibiotic for non-severe
community-acquired pneumonia recommended by the Spanish Society of Family Medicine
[12,13], and also endorsed by other scientific societies, such as the British Thoracic Society
[14], and the European Respiratory Society/European Society for Clinical Microbiology
and Infectious Diseases [15]. Although some clinical trials have compared amoxicillin with penicillin, these were
performed in children and with parenteral doses [16-19].

Methods

Study hypothesis and objectives

The main hypothesis of this study is that the administration of high doses of penicillin
V in patients with non-severe pneumonia attended in the community is not less effective
than high doses of amoxicillin (currently recommended treatment) in patients under
the age of 65 years without comorbidities. The main objective of this phase IV randomised,
multicentre, clinical, double-blind, parallel, clinical trial is to evaluate the efficacy
of phenoxymethylpenicillin (penicillin V) in the antibiotic treatment of non-severe
pneumonia attended in the community compared with amoxicillin, considering the rate
of clinical cure at 2 weeks. Secondary objectives are to assess the rate of radiological
cure at 4 weeks in the patients treated with the two antibiotics, evaluate the rate
of clinical cure at 4 weeks in both treatment groups, and evaluate the presence of
adverse effects in the patients treated with the two antibiotics.

Patient selection

Patients from 18 to 65 years of age without significant associated comorbidity attending
the primary healthcare centres or emergency departments with signs and symptoms of
lower respiratory tract infection and radiological confirmation of the diagnosis of
pneumonia will be recruited in this clinical trial. Exclusion criteria will be subjects
under 18 and over 65 years of age, severe impairment of signs (impairment of consciousness,
respiratory rate > 30 breaths/minute, heart rate > 125 beats/minute, systolic blood
pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg, temperature > 40°C, oxygen
saturation < 92%), hypersensitivity to β-lactams, important alteration on chest X-ray,
such as alveolar infiltrate in more than one lobe or bilateral, pleural effusion and/or
pulmonary cavitation, problems to comply with treatment at home – sociopathy or psychiatric
problems, drug and alcohol addiction, or within an inadequate family setting –, lack
of tolerance to oral treatment, such as the presence of nausea and vomiting, gastrectomy,
postsurgery and/or diarrhoea, significant comorbidity including bronchial asthma,
renal failure, hepatic cirrhosis, heart failure, chronic obstructive pulmonary disease,
ischaemic heart disease, stroke and/or type 1 diabetes mellitus, immunosuppression
– chronic HIV infection, transplantation, neutropenic, or patients receiving immunosuppressive
drugs or corticosteroids –, terminal disease, pregnancy or lactation, hospitalisation
in the last month, consumption of antibiotics in the last two weeks, difficulty to
attend the programmed visits or refusal to participate in the study.

Randomisation

Patients will be randomly assigned to either penicillin V 1,600,000 units (two 800,000-
unit pills) or amoxicillin 1,000 mg (two 500-mg pills) both taken thrice daily during
10 days. Subject numbers will be assigned sequentially as each subject enters the
study. The subjects will be assigned a study drug through a randomisation schedule
based on the randomisation plan. Since this is a multicentre study a block procedure
will be undertaken for the assignment of each primary care centre participating in
the study. Each container will include 66 pills (60 pills for the treatment plus 6
extra pills). The study drug, which will be prepared by the Pharmacy Unit of Hospital
Universitari Son Espases (Palma de Mallorca, Spain) and will be labelled with the
study number and a unique identification number.

Use of antithermic drugs or analgesics (acetaminophen, acetylsalicylic acid or ibuprofen),
bronchodilators as well as any medication, except oral systemic antibiotics, that
the patient is taking and which have been initiated prior to inclusion in the study
will be allowed. Since this is a clinical study no statistically significant differences
are to be expected in the concomitant treatment administered in the two treatment
arms. In the case of clinical deterioration, the investigating physician will administer
another antibiotic treatment in accordance with the clinical criteria.

Blinding issues

We will perform a double-blind clinical study in which neither the physician nor the
patient will know the treatment administered. The radiologists responsible for diagnosing
pneumonia and confirming the radiological cure will be also blind to the clinical
data and the treatment administered. The two medications will be presented as the
same type of capsule. This will ensure that even on opening the container no one will
know which medication has been given.

Withdrawal

Each participant will have the right to withdraw from the study at any time. In addition,
the investigator may discontinue a participant from the study at any time if the investigator
considers it necessary for any reason including significant protocol deviation, significant
non-compliance with the treatment regimen or study requirements (the patient will
be required to return all the medication samples not taken to the investigator; if
the remaining medication is not returned, compliance will be evaluated as insufficient),
an adverse event which requires discontinuation of the study medication or results
in inability to continue to comply with study procedures, disease progression which
requires discontinuation of the study medication or results in inability to continue
to comply with study procedures. In cases of clinical deterioration the medical investigator
will implement another antibiotic treatment considering the clinical criteria, withdrawal
of consent or loss to follow up.

Outcome measures

The variable of the main result will be clinical cure at 14 days, defined as absence
of fever, resolution or improvement of cough, improvement of general wellbeing and
normal respiratory auscultation or reduction of crackles indicating that no other
antimicrobial treatment is necessary. Any clinical result other than the anterior
will be considered as treatment failure. Variables of secondary results will be efficacy
at day 30 after the initiation of antibiotic treatment, radiological resolution or
improvement one month after the initiation of the treatment, complete clinical resolution
at day 14 defined as the total resolution of acute symptoms and signs related to the
infection, the presence of adverse events which may appear during the treatment, and
compliance with treatment administered. The radiologists responsible for diagnosing
pneumonia and confirming the radiological cure will be blind to the clinical data
and the treatment administered.

Ascertainment of visits

On fulfilling the inclusion criteria the nature of the study will be explained to
the patient and informed consent will be requested. All the eligible patients should
have a chest X-ray (posteroanterior and lateral projection) demonstrating pneumonic
infection. The study scheme and the visit program will be explained to the patient
(Table 1). The patients will be randomised to one of the 2 treatment groups and the medication
given. The first dose of the drug will be administered in the presence of the investigator.
They will be dispensed the drugs for ten days.

At the first follow-up visit, scheduled at day 3, a worsening of the clinical situation
of the patient will be evaluated to determine whether a change in the antibiotic treatment
is necessary. Likewise, compliance and possible secondary effects of the treatment
will be evaluated. At the second follow-up visit, at day 14, the clinical evolution
of the signs and symptoms will be evaluated and the need to change the antibiotic
treatment in the case of worsening in the clinical manifestations will be determined.
Likewise, compliance and possible secondary effects of the treatment will be evaluated.
The last follow-up visit, scheduled at day 30, the clinical outcome of the signs and
symptoms of the pneumonia will be evaluated and a new chest X-ray will be performed
(posteroanterior and lateral projection) to confirm radiological resolution of the
pneumonia. The medication will be discontinued in the case of clinical failure in
follow-up visits 2 and 3 or in the case of significant adverse events.

The variables will be registered in an electronic case report form designed by the
Hospital Universitari Vall d’Hebron (Barcelona, Spain). The variables considered in
this trial will be sociodemographic (birth date, gender, race) and toxic habits (smoking
and drinking behaviours), present medical history (presence and duration of signs
and symptoms: fever, cough, expectoration, sputum purulence, diarrhoea, malaise, muscular
aches, joint aches, thoracic pain, dyspnoea, respiratory auscultation; and details
of any history of high blood pressure, type 2 diabetes mellitus or hypercholesterolemia),
physical examination (axillary temperature, resting pulse, respiratory rate, blood
pressure measurements, oxygen saturation, and auscultation abnormalities) and X-ray
findings.

Sample size

The objective of the study is to demonstrate that penicillin V is not inferior to
amoxicillin. Considering a success rate of 85% for the group treated with amoxicillin
[20,21] a total of 105 patients will be required in each treatment group (total of 210) to
detect a non-inferiority margin of 15% at maximum between the two treatments with
a minimum power of 80% considering an alpha error of 2.5% for a unilateral hypothesis
and maximum possible losses of 15%.

Statistical analyses

The intention-to-treat (ITT) population will include all randomised patients receiving
at least one dose of study drug and the per-protocol (PP) population will include
patients receiving no systemic antimicrobial agents other than the study drug for
at least three days in the case of clinical failure or ≥80% of study medication in
the case of cure, with adequate assessment of compliance and absence of major protocol
violations.

To evaluate the comparability of the groups the two groups will be analysed with variables
expressed as means and standard deviations for the case of quantitative variables
and with proportions in the case of qualitative variables. The variable of the principle
result, clinical cure, will be expressed as percentages and the comparison of percentages
in the two treatment groups will be analysed using the Chi-square test. Logistic regression
will be performed for the analysis of the predictive factors of cure or not, with
calculation of the odds ratio for each of the variables analysed and multiadjustment
for each of the factors of the study with confidence intervals of 95%. Variables with
a p<0.20 on bivariant analysis will be included in the analysis. A p value < 0.05
will be considered statistically significant.

Limitations and strengths

The main limitation of this study is that the microbiological study is not taken into
account. This study will be carried out within the primary care setting in which 80%
of community-acquired pneumonias are treated. Bacterial eradication has been considered
a secondary outcome in many studies undertaken up to now. In a recent review published
by Gilbert this measure was not recommended in mild-moderate pneumonia [22]. Despite the use of aggressive tests such as serological analysis, sputum samples,
blood cultures, etc., to identify the causal agent of pneumonia, the causative microorganism
of the pneumonia is only identified in 20% of ambulatory cases. Moreover, primary
care physicians judge the response to treatment with eminently clinical but not with
microbiological criteria. Neither is the return to daily activities of the patients
considered because of the coexistence of variables which cannot be controlled and
which cannot be generalised to other countries. The percentage of referral to hospital
will not be taken into account since many other confounding variables lay behind this
variable in a study of these characteristics. Neither will blood tests be carried
out. Although they may feasibly be done within the primary care setting, they are
not justified in this study since this is not a study on safety.

This study will be undertaken in several health care centres with an investigator-monitor
figure in each. Previous meetings with the investigators and all the participating
physicians of the different health care centres will allow the homogeneity necessary
to carry out the study.

Because penicillin is seldom used in our country and because such a high dose of penicillin
is even less prescribed, a Data and Safety Monitoring Board will be created, constituting
a strength of the study. An independent group of experts will be responsible for monitoring
patient safety and treatment efficacy data during recruitment. From a microbiological
standpoint, bacterial eradication is achieved when the concentration of antibiotic
is above 40-50% of the time between β-lactams dose intervals. For partially resistant
strains, it is recommended that this time be above 60% [23]. We know that the bioavailability of penicillin V is very variable, ranging from
25% and 60%. The concentration of penicillin measured 1–3 hours after the last consumption
of a 250-mg penicillin V regimen taken four times daily for 3–4 days is 0.1 - 2 μg/ml
[23]. One study found that the MIC achieved with penicillin V is higher than with penicillin
G administered parenterally [24]. In a study carried out in Sweden, Fredlund et al. showed that oral penicillin V is as effective as parenteral penicillin in patients
with community-acquired pneumonia when the former is administered during ten days
[25]. In the Scandinavian countries, where penicillin V is considered as the first choice
for uncomplicated pneumonia [1], high doses ranging from 1 million to 1.5 million units thrice-daily are recommended
[26,27]. The dose of 1.6 million units has been chosen in our study, since the percentage
of intermediate pneumococcal resistance strains is much greater in Spain than in the
Scandinavian countries. According to data from the European Centre for Disease Prevention
and Control for the year 2011, intermediate pneumococcal resistance to penicillin
was 20.4% in Spain, 4.6% in Denmark, 3.4% in Norway and 0.3% in Sweden [28]. Regarding the safety of the regimen of 1.6 million units (corresponding approximately
to 1 gram of penicillin V) thrice-daily, although this dose is not marketed in our
country, a presentation of 1.5 million units is available in Scandinavian countries.
In addition, the British National Formulary recommends doses of up to 1 gram of penicillin
V every 6 hours [29]. For this reason, we think that the dose of 1.6 million units taken thrice daily
is fully justified in this clinical trial.

Ethical aspects

The study will be conducted in accordance with the principles of the Declaration of
Helsinki, ICH Guidelines for GCP and in full conformity with prevailing regulations.
The study has been approved by the Ethical Committee of Investigation in Primary Care
in Catalonia (Fundació d’Investigació en Atenció Primària) (protocol code: IJP–PEN-2012) (Additional file 1) and by the Agencia Española del Medicamento y Productos Sanitarios. This study does not require the use of unusual, additional tests: only a chest X-ray
will be undertaken to rule out a pneumonic process, being a test that is total justified
in this project. From an ethical point of view, this is to certify that the objective
of this study is important and relevant for primary care, the power of the study may
be considered as reasonable, this is an original study, the risks which the participants
may incur justify the investigation being carried out with a totally favourable benefit/risk
quotient, and we ensure the external validity of the study to the primary care reality,
with the inclusion and exclusion criteria described. Vulnerable populations will not
be participating in this study and neither will economic compensation be given to
patients for their participation. The investigators will be free to publish the results
of this study, regardless of the results obtained.

The trial staff will ensure that the anonymity of the participants is maintained.
The participants will be identified only by a participant number on the consent report
form and an electronic database. All documents will be stored securely and only accessible
by trial staff and authorized personnel. The study will comply with the Data Protection
Legislation which requires data to be anonymised as soon as it is mandatory to do
so.

Discussion

In this study, interventions and follow-ups will be similar to clinical practice.
We believe that the methodology used is very simple as it should be in primary care.
The data collection has been simplified to facilitate the inclusion of cases in primary
care offices. Chest x-ray is absolutely necessary to confirm the diagnosis of pneumonia
and will therefore be an essential requisite for inclusion of the patients to thereby
avoid the inclusion of patients who do not have the disease. Secondly, this study
will be undertaken in several health care centres with an investigator-monitor figure
in each. The antibiotics used in this study have been in the Spanish pharmaceutical
market for more than 30 years, being amoxicillin the first-drug of choice in our guidelines
for the treatment of pneumonia in the community setting in adults under 65 years [12,13]. Therefore, the principle of equipoise is guaranteed in this clinical trial. Since
the dose of penicillin considered in this trial is high and infrequently used in our
country, a Safety Board will be the responsible body to monitor the adverse events
that might be present during the development of the trial, thereby ensuring the safety
of the patients recruited. Only uncomplicated cases of pneumonia that could be treated
in the community will be taken into account. Even though patients with certain comorbidities
such as high blood pressure or type 2 diabetes mellitus might be included in this
trial we believe that the sample size and the randomised, double-blind methodology
used in this study will eliminate a possible selection bias.

This study may have a socioeconomical impact. If treatment with penicillin demonstrates
to be as effective as that of amoxicillin in uncomplicated community-acquired pneumonia,
this will have a considerable socioeconomic impact. It may also have an impact on
the treatment of other respiratory tract infections. Most prescriptions of amoxicillin
and amoxicillin-clavulanate are prescribed for respiratory tract infections [3]. If treatment of the most severe respiratory infection (pneumonia) with penicillin
is found to be as effective as that with a broad-spectrum β-lactam, this would aid
in adopting a more rational use of antibiotics in respiratory infections mainly caused
by pneumococci. Both the amount of antibiotics used and how they are used contribute
to the development of resistance. The use of broad-spectrum antibiotics rather than
narrow-spectrum drugs is known to favour the emergence of resistance by broadly eliminating
competing susceptible flora [30]. If the efficacy of penicillin is comparable to the first-choice drug for this infection
we will be able to encourage the use of narrower-spectrum antibiotics for treating
pneumococcal respiratory tract infections. On the other hand, penicillin V is less
expensive in our country and this would therefore also aid in reducing drug costs
for the treatment of this infection.

Competing interests

The authors declared that they have no competing interest.

Authors’ contributions

CL and JA conceived the study. CL, JA, RM, AGS, JL and MGS contributed to the planning
of the study. CL was responsible for drafting the paper. All authors revised and approved
the final version of the manuscript.

Acknowledgements

This study has received external funding by an independent academic institution (Instituto de Salud Carlos III, Spanish Ministry of Science, grant PI11/02471), without any other source of funding.
The funding body has had no role in the design of this study.